Titanium has been successfully used for decades in dental and orthopedic implants, but the exact mechanism of successful osseointegration has not been determined. We will investigate the hypothesis that the biocompatibility of titanium involves an interaction between the surface layer of titanium dioxide on the metal implant and reactive oxygen mediators of the inflammatory response in model systems with varying degrees of complexity. Different forms of surface oxide can exist on titanium, and the relationship between defined surface oxides and anti-inflammatory response will be determined. We recently demonstrated that peroxynitrite, a highly reactive compound and inflammatory mediator produced in vivo by the reaction of the free radicals nitric oxide and superoxide, is significantly degraded by titanium oxides. Furthermore, there appears to be a strong correlation between the ability to degrade peroxynitrite and ultimate in vivo biocompatibility. Specific Aim 1 will examine the ability of titanium and other oxides to inhibit the reactivity of reactive oxygen species and peroxynitrite. In Specific Aim 2, well-defined and characterized thin films of titanium oxide and other metal oxide surfaces will be fabricated on quartz, stainless steel and thermoset silicone substrates and the interaction of stimulated polymorphonuclear leukocytes and macrophages with these surfaces will be investigated to determine if these fabricated surfaces can inhibit the response of inflammatory cells. In Specific Aim 3, in vivo experiments will correlate this ability with the inflammatory response in both normal and arthritic rat models. The proposed experiments will compare the ability of titanium oxide to inhibit inflammatory reactive oxygen species compared with other materials and determine whether this property can be conferred onto other surfaces. We will determine if there is a correlation between the results of the chemical reaction kinetics on surfaces of defined crystalline and chemical composition in Specific Aim 1, and the in vitro cellular responses to these surfaces in Specific Aim 2, with the longer-term in vivo responses in Specific Aim 3. If a positive correlation is demonstrated, we will have established that antioxidant properties of biomaterials as a predictor of in vivo biocompatibility. Our long-term goal is to extend this knowledge to develop new biocompatible materials with superior mechanical and material properties than titanium.